Protein Kinases are involved in very complex signaling cascades that regulate most cellular functions, including survival and proliferation. These signaling pathways have been heavily studied, particularly in the context of disorders caused by dysregulated cellular function, such as cancer. The extracellular signal-regulated kinases (ERKs) are one class of signaling kinases that are involved in conveying extracellular signals into cells and subcellular organelles. ERK1 and ERK2 (ERK1/2) are kinases in the mitogen activated protein kinase (MAPK) pathway, and are also referred to as p42 and p44, respectively. ERK1 and ERK2 are present in relatively large quantities in cells (˜107 molecules per cell), and are involved in regulating a wide range of activities. Indeed, dysregulation of the ERK1/2 cascade is known to cause a variety of pathologies including neurodegenerative diseases, developmental diseases, diabetes and cancer. Wortzel and Seger, Genes & Cancer, 2:195-209 (2011), published online 9 May 2011.
The role of ERK1/2 in cancer is of special interest because activating mutations upstream of ERK1/2 in its signaling cascade are said to be responsible for more than half of all cancers. Id. Moreover, excessive ERK1/2 activity was also found in cancers where the upstream components were not mutated, suggesting that ERK1/2 signaling plays a role in carcinogenesis even in cancers without mutational activations. The ERK pathway has also been shown to control tumor cell migration and invasion, and thus may be associated with metastasis. See A. von Thun, et al., ERK2 drives tumour cell migration in 3D microenvironments by suppressing expression of Rab 17 and Liprin-β2, J. Cell Sciences, online publication date 10 Feb. 2012. In addition, it has been reported that silencing either ERK1 or ERK2 using shRNA killed melanoma cells in culture, and also made melanoma cells more sensitive to inhibitors of BRAF. J. Qin, et al., J. Translational Med. 10:15 (2012). Indazole derivatives acting as ERK inhibitors have been reported as therapeutics for treating cancers. WO2012/118850; WO2012/030685; WO2007/070398; WO2008/153858. Certain bicyclic systems having pyrazole fused to a pyrrolidine ring are known in the art also—see e.g., WO2006/072831, WO2012/065935—and have been reported to inhibit other kinases. However, there remains a need for new therapeutic agents that inhibit ERK1 and/or ERK2 to treat disorders associated with undesired levels of ERK1/2 activity, particularly in cancers where mutations elsewhere in the MAPK pathway promote resistance to inhibitors of other pathway enzymes including Raf and MEK. The current invention provides novel fused pyrrolidine compounds that inhibit ERK1, ERK2, or preferably both (dual inhibitors), for use to treat diseases such as cancer that are associated with activation of ERK1 and/or ERK2, and especially for MAPK pathway dependent cancers showing resistance to Raf and/or MEK inhibitory cancer therapeutics.